Botulinum toxin A versus microwave thermolysis for primary axillary hyperhidrosis: A randomized controlled trial

Background Botulinum toxin A (BTX) and microwave thermolysis (MWT) represent 2 treatment modalities for axillary hyperhidrosis with different procedural and efficacy profiles. Objective To compare long-term outcomes following BTX vs MWT treatment of axillary hyperhidrosis. Methods A prospective, randomized, within-patient, controlled trial, treating axillary hyperhidrosis with contralateral BTX and MWT. Objective sweat measurement and patient-reported outcome measures for sweat and odor were collected at baseline, 6-month and 1-year follow-up (6M/1YFU). Hair reduction and patient treatment preference was also assessed. Results Sweat reduction was significant (all P <.01) for both interventions throughout the study. Objectively, sweat reduction was equal at 1-year FU (ΔP =.4282), but greater for BTX than MWT at 6-month FU (ΔP =.0053). Subjective sweat assessment presented comparable efficacy (6MFU: ΔP =.4142, 1YFU: ΔP =.1025). Odor reduction was significant (all P <.01) following both interventions, whereas only sustaining for MWT (6MFU: ΔP =.6826, 1YFU: ΔP =.0098). Long-term, hair reduction was visible after MWT, but not BTX (ΔP ≤.0001), and MWT was preferred by the majority of patients (76%). Limitations The intrinsic challenges in efficacy assessment. Conclusion This study exhibited BTX and MWT with similar sweat reduction, but distinguishable odor and hair reduction at 1-year FU. These findings support individualized treatment approaches for axillary hyperhidrosis based on patient-specific symptoms and preferences.


INTRODUCTION
Primary axillary hyperhidrosis is present in $2% of the general population 1 and is known to generally based on the objective gravimetric test, 3 but patient-reported outcome measures (PROMs) are gaining more ground as they can assess the impact of both sweat, odor, and QoL in a standardized way.
The condition is managed through a wide variety of treatments, including topicals, systemic treatments and procedures as injectables, energy-based devices, and surgery. 4Different treatment options allow increasingly tailored treatments with focus on patient-specific symptoms and preferences.
Botulinum toxin A (BTX) has gained its place as standard treatment for focal hyperhidrosis in the past decades.Intradermal toxin injections induce blockage of acetylcholine release and hence the neuronal signal to sweat glands. 5[8][9][10] Microwave thermolysis (MWT) is a newer, energybased treatment that irreversibly targets the sweat glands by delivering thermal energy to the dermal-fat interface. 11,12The device offers an alternative efficacy profile for axillary hyperhidrosis as well as osmidrosis and hair reduction [13][14][15] that may be permanent.
][13][14][15][16] However, in the light of the increasing demand for individualized treatment approaches, there is a lack of direct comparison of BTX and MWT in terms of clinical profile, efficacy and longevity, especially.
This study aimed to do a long-term side-by-side comparison of BTX and MWT for axillary hyperhidrosis, with both objective and subjective outcome measures, for the elucidation of the treatments' individual procedural and efficacy profile, highlighting similarities and distinctions.

Design
This study was a prospective, randomized, withinpatient, controlled trial of axillary hyperhidrosis treatment with BTX vs MWT at baseline followed by a telephone survey on day 2 and clinical follow-up (FU) up to 6-months and 1-year posttreatment.
The GCP-monitored trial was carried out between 3rd quartile 2021 and 2nd quartile 2023 at the Department of Dermatology, Copenhagen University Hospital, Denmark, and conducted in accordance with the Helsinki Declaration.

Population
Adults with confirmed primary axillary hyperhidrosis at baseline, with a positive gravimetric test (women: $50 mg/5 minutes, men: $100 mg/5 minutes) and subjective rating of 3 or 4 on the Hyperhidrosis Disease Severity Scale (HDSS), were included.
Exclusion criteria comprised presence of generalized hyperhidrosis, medicine known to affect sweat secretion, pregnancy or lactation, previous axillary surgery, other medical condition in axillae, contraindications for BTX or MWT, history of intolerance to utilized medicinal products, and other hyperhidrosis treatment prior to inclusion defined as follows: topical prescription medication (#10 days), systemic treatment (#10 days), BTX (#12 months), and MWT (ever).
Simultaneous therapy was not allowed, except for over-the-counter antiperspirants up until 1 to 5 days (type-dependent) before study visits.

Interventions
All baseline treatments were performed by a single, trained clinician (GLG), treating one axilla with BTX and the contralateral with MWT.
Computerized randomization, equally distributing treatments between right/left axilla in blocks of 6, was performed by an independent data analyst and then kept in sealed, opaque envelopes until revealed in the given baseline session.
Treatment areas were assessed individually and defined by the anatomic features, including the

CAPSULE SUMMARY d
Botulinum toxin A and microwave thermolysis for axillary hyperhidrosis have been investigated individually, whereas this side-by-side trial provides comparable evidence of their advantages and limitations.The clinical profiles of botulinum toxin A and microwave thermolysis differ significantly and should induce an individualized treatment approach depending on patient-specific symptoms and preferences.
visual full hair-bearing area, and supported by the starch-iodine test.
BTX treatment was executed with the commercially available Botox (Allergan Pharmaceuticals plc) with a standard 50 to 100 units (in 3-6 mL isotone sodium-chloride solution) per axilla depending on individual site size.
The miraDry-system (miraDry Inc) was utilized for the MWT treatment with standard setting of energy level 5 (5.8 GHz, 3.0 seconds) and standardized tumescent anesthesia of 70 to 124 mL (lidocaineadrenaline [50 mL; 10 mg/mL 1 5 g/mL] in sodiumchloride solution) per axilla based on size and individual anesthetic effect.

Patient characteristics
Demographics included age, sex, body mass index, and history of treatment with study interventions.Outcome measures were individually assessed for each axilla at baseline, 6-month and 1-year FU.Additionally, possible adverse effects were surveyed throughout the study duration.

Objective outcome measures
Gravimetric test.Efficacy assessment for sweat was conducted with gravimetric testing using standardized filter paper (Whatman Ashless Quantitative Filter Paper, 9.0 cm diameter, grade 40).For all the tests, patients were in resting position in normal room temperature and had avoided antiperspirants $24 hours before testing.Weighing the filter paper before and 5 minutes after placement, at least one axilla produced $50 mg/5 minutes for women and $100 mg/5 minutes for men for a positive gravimetric test result, and the contralateral axilla at minimum 20% below the sex-specific threshold.
Starch-iodine test.Clinical visualization was collected with a digital camera, both with and without the starch-iodine test, which appears as purple-black coloration by application of iodine and corn starch in contact with sweat.The test supported the clinical assessment of treatment area.
Hair reduction.Axillary hair reduction following BTX and MWT until 1-year FU was each assessed by the clinician, supported by clinical images, on a 3-point scale (0-3: 0: none, 1: light, 2: moderate, and 3: severe) compared with baseline.

Subjective outcome measures
PROMs.PROMs were collected for the assessment of subjective efficacy and included the HDSS, a 4-point scale for sweat, Odor Scale, a 10-point scale for malodor, and Dermatology Life Quality Index (DLQI), a 10-item questionnaire (max score 30), as well as Hyperhidrosis Quality of Life Index (HidroQoL), an 18-item questionnaire (max score 36).In all scales, high scores represented negative outcome and low scores positive outcome for the patient.See PROM scales overview in Fig 1 .Pain.Procedural pain during the treatment session was assessed for BTX and MWT on a standard 10-point Numerical Rating Scale.Postprocedural pain following BTX and MWT, was each assessed on a 3-point scale (0-3: 0: none, 1: light, 2: moderate, and 3: severe) on day 2 (telephone survey), and at clinical FU visits.

Statistics
Sample size calculation was based on the HDSS scale (1-4) with the expected, clinically meaningful change to be $1.0.Using calculations for a 2-tailed test of hypothesis (a = 0.05, power = 80%, SD = 1.2) the sample size was deemed to be 23 subjects.Considering a possible 25% drop out, 30

Patient characteristics
A total of 30 patients with primary axillary hyperhidrosis were included and completed the study.Two-thirds were women and one-third were men with overall median age of 26 years.Prior to study participation, no patients had received MWT treatment (per protocol), whereas 8 (27%) had previously received BTX-treatments.See Table I for demographic overview.
All patients received a single baseline treatment with BTX in one axilla and MWT in the contralateral, according to the randomization.There was no significant downtime and no unexpected side effects following either intervention throughout the study, and no serious adverse events were registered.
Starch-iodine test.Supporting the objective findings, starch-iodine test was performed at baseline and FU for an instantaneous visualization of axillary sweat.As exemplified in Fig 2, similar sweat at baseline was visibly reduced bilaterally at 1-year FU with characteristic patterns for BTX and MWT, respectively.
Patient satisfaction and preference.Patients were asked to provide overall treatment satisfaction; 24 (80%) were satisfied, 2 (7%) were indecisive, and 4 (13%) were not satisfied due to insufficient effect on both sweat and odor.
At end of study, patients were asked about their treatment preference for their continued individual approach, when taking all into account; procedure, side effects and efficacy.MWT was preferred by 23 (76%), BTX preferred by 5 (17%), while 2 (7%) were indecisive.There was no sex-specific preference difference.

DISCUSSION
This study conducted a side-by-side comparison of BTX and MWT for axillary hyperhidrosis in a randomized, controlled trial with 1-year FU.Both treatments effectively improved axillary sweat, odor as well as QoL.While BTX performed objectively better than MWT for sweat reduction at 6month FU, they performed similarly on sweat reduction at 1-year FU.In contrast, odor reduction at 6-months was similar, but at 1-year FU, odor reduction started to revert on the BTX-side, while it sustained on the MWT-side.On-site procedural pain was higher for BTX, whereas postprocedural pain was only reported for MWT.Furthermore, hair Table II.Objective measure of sweat intensity by gravimetric test at baseline, 6-months, and 1-year following botulinum toxin A and microwave thermolysis, presented with medians (IQR) and %-decrease Grove et al 95 reduction was the sole long-term side effect, only seen after MWT.
The patients in this study showed a distinctive preference for MWT at the end of study.Most patients reported that acceptable efficacy with MWT, combined with the possibility to avoid continuous treatment, was preferred.Some patients preferred the short-term efficacy of BTX, whereas others did not experience satisfactory effect of either treatments, but mainly pursued a second MWT treatment, poststudy.Eight patients had previous BTX treatment, but the majority were na€ ıve to both treatments before inclusion.

Strengths and limitations
The randomized, controlled trial design was the main strength of this comparative investigation, but blinding was not feasible.Follow-up time up to 1 year was long, but even longer FU, allowing BTX to wear off completely, could have added to the study findings.Patients were included exclusively on hyperhidrosis parameters, and as such the difference in odor reduction may have been bigger with osmidrosis as an additional inclusion criteria.
The standardized collection of both objective and subjective measures provided broader and more credible outcome assessment than with either measure, individually.Efficacy assessment is complicated, however, by the nature of this condition, existing within a spectrum from normal to pathologic sweating, varying significantly over the course of a day.Despite the intraindividual design, the intrinsic challenges with the objective gravimetric test is a limitation, and coherently, PROMs also underlie risk of bias. 17Although PROMs scales have proven to be useful in this patient group, 16,[18][19][20][21][22] the patients' ability to distinguish between sides is dependent on the respective scale properties.For the QoL scales, specifically, it did not appear that patients were able to significantly distinguish between the 2 sides, despite noticeable differences in both sweat and odor over the course of the study.

Perspectives
A progressive demand and focus on individualized treatment pillars clinicians' effort toward better outcomes and increased patient satisfaction.Patients consider both efficacy and side effects, especially long-term.While pain will be the main concern for some, others will predominantly be impatient for immediate and/or long-term efficacy.A prior study on MWT confirmed that side effects are generally temporary and that patients are able to accept these in exchange of satisfactory efficacy. 16Because of the different clinical efficacy profiles, some patients may prefer and/or clearly benefit more from one treatment than the other.Additional outcomes, such as hair reduction, can even be desirable to some Grove et al 97 patients, whereas others may have a specific aversion to this.
Although rare, serious adverse events have been reported both to BTX and MWT.It remains important to take these into account for optimal, individualized treatment plans.
Long-term use of BTX may increase the risk of toxic effects which appears to be highly dose dependent, and adverse events are reported more common with therapeutic BTX use than cosmetic use. 235][26] For hyperhidrosis, specifically, BTX has been described to cause botulism-like generalized weakness. 27Fatal outcomes have been related to local or systemic toxin spread causing respiratory arrest, gangrene or anaphylaxis. 24,28,29Notably, patients with neuromuscular diseases are more vulnerable to BTXrelated adverse events. 26reatment with microwave devices can cause potentially serious adverse events, and infections are the most common, while burns and neurologic complications have also been reported. 30A case with fatal necrotizing fasciitis following nonstandardized MWT of alternative treatment areas has been described. 313][34][35] Current standard MWT treatment includes extensive tumescent anesthesia for reducing the risk of neuropathy. 36][39] The risk of serious side effects cements the importance of these treatments being provided by health care professionals that can take medical history, including drug allergies and contraindications, into account as well as assure relevant prevention and handling of possible serious complications.
Optimizing the patient experience is the key to increased patient satisfaction, whether it be based on efficacy, alone, or the possible side effects as well as additional outcomes.The clinical profile of each tailored treatment option, the patient needs and medical history, as well as the patient expectations should be considered.

CONCLUSION
This study adds evidence to treatment similarities and distinctions with a direct comparison of BTX and MWT up to 1-year FU.Treatment with BTX vs MWT present with very different clinical profiles and the patients' focus and preference in this study were the long-term outcomes.The findings are relevant for future patient information, useful for patientinvolvement in shared decision-making, and support the increased demand for individualized treatments based on patient-specific symptoms and preferences. d

Fig 2 .
Fig 2. Sweat intensity visualized by starch-iodine test at baseline and 1-year following botulinum toxin A and microwave thermolysis in 1 study patient.

Fig 3 .
Fig 3. Axillary hair growth 1-year following botulinum toxin A and microwave thermolysis (MWT); examples of visible hair reduction in 3 study patients with (A) light, (B) moderate, and (C) severe hair reduction on the MWT-treated axilla.

Fig 4 .
Fig 4. Subjective measures of sweat, odor, and quality of life at baseline, 6-months and 1-year following botulinum toxin A and microwave thermolysis, presented with medians (IQR) and DP values.